Microwave-assisted condensation of kojic acid with aldehydes

Article abstract of DOI:10.3184/174751912X13383100102119

Kojic acid derivatives have been prepared in excellent yield by the condensation of two molecules of kojic acid and one molecule of an aldehyde using sodium carbonate as a base under microwave irradiation.

Full text of DOI:10.3184/174751912X13383100102119

450 RESEARCH PAPER
AUGUST, 450–452
JOURNAL OF CHEMICAL RESEARCH 2012
Microwave-assisted condensation of kojic acid with aldehydes
Pan-Pan Hua, Chun-Feng Zhub and Tao Zhoua*
aSchool of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang 310035, P. R. China
bCollege of Pharmaceutical Sciences, Zhejiang University ofTechnology, Hangzhou 310014, P. R. China
Kojic acid derivatives have been prepared in excellent yield by the condensation of two molecules of kojic acid and
one molecule of an aldehyde using sodium carbonate as a base under microwave irradiation.
Keywords: kojic acid, aldehyde, microwave irradiation, condensation
Tyrosinase is a multi-functional copper-containing enzyme
which is widely distributed in microorganisms, plants and
animals.1 It is a key enzyme in the biosynthesis of melanin
and is responsible for melanization in animals and browning
in plants.2 Thus tyrosinase inhibitors have been widely used
in the agricultural, food, cosmetic and medicinal fields.3
Kojic acid, 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (1)
possesses appreciable inhibitory activity against tyrosinase
by chelating copper, which is associated with its γ-pyrone
structure containing an enolic hydroxyl group.4 Kojic acid also
exhibits free radical scavenging activity and prevents photo-
damage.5 Kojic acid has been used as an ingredient in cosmet-
ics and as an anti-browning agent in foods that change colour
easily.6,7 The synthesis of kojic acid derivatives have attracted
considerable attention recently.8–12 In attempts to seek better
tyrosinase inhibitors, Barham et al reported13 the reaction
of kojic acid with aldehydes in the presence of ammonia in
ethanol, which needed long reaction time (up to 48h) and
a relatively complicated purification. Thus, a simple and
efficient method for the preparation of the corresponding kojic
acid derivatives is required.
In recent years, microwave-assisted organic reaction has
become a widely-used and valuable technique in organic syn-
thesis with considerable advantages over conventional thermal
methods.14 The beneficial effects of microwave radiation on
performing organic reactions are well known, for example
affording remarkable reductions in reaction time, improved
yields and easier workups.15–19 We report here a convenient
and efficient synthesis of kojic acid derivatives by the
condensation of kojic acid with aldehydes under microwave
irradiation.
Two solvent systems, water/methanol and water/ethanol, were
tested in the reaction. It was found that the reaction proceeded
much better in water/methanol than in water/ethanol. The
effect of volume ratio of water/methanol was also tested, and
the best result was obtained when water/methanol ratio was
1:1. Among the tested bases, Na2CO3 was found to be best
choice for the preparation of 3a. The effect of molar ratio of
starting materials kojic acid/pentanal on the reaction was
investigated. In the case of molar ratio of 2:1 which is required
for the formation of 3a, the product which was obtained, was
found to be contaminated by a small amount of unreacted kojic
acid after work-up (entry 9). This is probably due to the side
reactions which consumed some pentanal. Increasing the
amount of pentanal to a molar ratio of 1:1 improved the yield
of 3a and the kojic acid reacted completely (entry 8). The yield
of 3a reached a maximum when molar ratio of kojic acid/
pentanal was 1:1.5 (entries 10 and 11). A study on the effect of
reaction time showed that the reaction was completed after 3h
at 70 °C to give 3a in good yield (entries 10 and 12). Thus, the
optimal reaction conditions for the synthesis of 3a at 70 °C are:
water/methanol (1:1) as solvent, sodium carbonate as a base,
molar ratio of kojic acid/pentanal 1:1.5, reaction time 3h.
In order to further improve the yield, we investigated the
reaction of kojic acid and pentanal under microwave irradia-
tion. The other optimised reaction conditions such as molar
ratio of kojic acid:pentanal (1:1.5), sodium carbonate as a base
and water:methanol (1:1) as solvent, were retained in this
investigation. The effects of MW power and reaction time on
the reaction were examined. The results are shown in Table 2.
The best yield was obtained at 400W (entry 2). It was found
that the yield of 3a was improved significantly when the reac-
tion time was prolonged to 40 min (85% yield) compared to
30 min (entries 2 and 5), but further extension of the reaction
time did not improve the yield (entry 6). The optimal condi-
tions for obtaining 3a under microwave irradiation involved
the use of 400 W power microwave at 70 °C and reaction time
Results and discussion
Initially, we examined the reaction of kojic acid (1) and
pentanal (2a) under different reaction conditions. In some
cases, both the condensation product of two molecule of kojic
acid with one molecule of pentanal (3a) and the condensation
product of one molecule of kojic acid with one molecule of
pentanal (4a) were detected (Scheme 1). However, in those
cases, after work-up 3a and 4a were obtained as a mixture,
which was difficult to separate by recrystallisation. In order to
optimise the reaction conditions for the preparation of pure 3a,
we investigated the effects of several factors including the
molar ratio of kojic acid to pentanal, reaction time, base and
solvent on the products. The results are presented in Table 1.
Table 1 The reaction of kojic acid with pentanal under different
reaction conditionsa
Entry
Solvent
Base
Time Ratio of Yield/%b
/h
1/2a
3a
4a
1
2
H2O/MeOH(1:1) Na2CO3
H2O/EtOH(1:1) Na2CO3
2
3
2
2
5
5
3
3
3
3
3
5
1:1
1:1
52
28
32
35
42
12
15
12
16
15
3
H2O/MeOH(1:2) Na2CO3
H2O/MeOH(2:1) Na2CO3
H2O/MeOH(1:1) NaOH
H2O/MeOH(1:1) NaHCO3
1:1
4
1:1
5
1:1
6
1:1
Trace Trace
70 None
72 None
69c None
75 None
75 None
76 None
7
H2O/MeOH(1:1)
K2CO3
1:1
8
H2O/MeOH(1:1) Na2CO3
H2O/MeOH(1:1) Na2CO3
H2O/MeOH(1:1) Na2CO3
H2O/MeOH(1:1) Na2CO3
H2O/MeOH(1:1) Na2CO3
1:1
9
2:1
10
11
12
1:1.5
1:2
1:1.5
a All reactions were carried out at 70 °C.
Scheme 1
b Yield based on kojic acid.
* Correspondent. E-mail: taozhou@zjgsu.edu.cn
c Contaminated by trace amount of kojic acid.

JOURNAL OF CHEMICAL RESEARCH 2012 451
Experimental
Table 2 The reaction of kojic acid with pentanal under micro-
wave irradiationa
1H NMR data were recorded on a Bruker Avance 400 spectrometer
using DMSO-d6 as the solvent with TMS as an internal standard. IR
spectra were determined on NICOLET 380 IR spectrometer with KBr
pallet. ESI-MS spectra were recorded on 4000Q mass spectrometer
(Applied Biosystems, USA). High resolution mass spectra (HRMS)
were obtained on a QTOF Micro using the ESI source. Melting points
were measured on SGW X-4 micro melting point apparatus and are
uncorrected. Microwave irradiation was carried out in a XH-MC-1
microwave synthesiser.
Entry
MW power W Time/min
Product
Yield/%b
1
2
3
4
5
6
200
400
600
800
400
400
30
30
30
30
40
50
3a
3a
3a
3a
3a
3a
NDc
69
66
63
85
85
a All reactions were run with kojic acid (10mmol), pentanal
(15mmol), Na2CO3 (10mmol), H2O/MeOH (1:1, 20mL) at 70 °C.
b Isolated yield based on kojic acid.
Synthesis of 3,3′-dihydroxy-6,6′-bis(hydroxymethyl)-2,2′-(pentane-
1,1-diyl)di-4H-pyran-4-one (3a)
c Not determined as a mixture of 3a and 4a was obtained.
Under conventional thermal conditions: Pentanal (15 mmol) was
added to a mixture of kojic acid (1.42 g, 10 mmol), sodium carbonate
(1.06 g, 10 mmol) in water (10 mL) and methanol (10 mL) was added
pentanal (15 mmol) at 70 °C. The reaction mixture was stirred at this
temperature for 3h. After removal of about half the volume of the
solvent, the solution was neutralised to pH1 with concentrated hydro-
chloric acid Dichloromethane (30 mL) was then added. The product
3a precipitated after 30 min and was collected by filtration as an off-
white solid (1.32, 75%). Further purification was achieved by recryst-
allisation from ethanol. M.p. 186.2–187.3 °C (lit.13 185.6–187.2 °C);
IR (KBr) νmax: 3443, 3304, 2925, 1647, 1617, 1571, 1450, 1322, 1221
cm−1; 1H NMR (DMSO-d6, 400 MHz): δ 0.87 (t, J = 8.0 Hz, 3H, CH3),
1.20–1.34 (m, 4H, CH2), 1.93 (q, J = 8.0 Hz, 2H, CH2), 4.30 (s, 4H,
CH2), 4.70 (t, J = 8.0 Hz, 1H, CH), 5.66 (br, 2H, OH), 6.30 (s, 2H,
C-5H in pyran ring), 9.10 (br, 2H, OH); 13C NMR (DMSO-d6,
100 MHz): δ 13.7 (CH3), 21.6 (CH2), 28.5 (CH2), 28.8 (CH2), 35.5
(CH), 59.4 (CH2), 108.7 (C5H in pyran ring), 142.0 (C2 in pyran ring),
148.0(C3 in pyran ring), 167.4(C6 in pyran ring), 173.4(CO in pyran
ring). ESI-MS: m/z 353 (MH+).
40 min. In comparison with the conventional thermal method,
the yield of 3a was increased from 75 to 85% with the aid of
microwave irradiation.
We investigated the scope of the reaction of kojic acid with
a range of aldehydes including both aliphatic and aromatic
aldehydes under the above optimal reaction conditions with
microwave irradiation (Scheme 2). It was found that the reac-
tion proceeded smoothly and gave the desired product 3 in
excellent yields. The results are summarised in Table 3. As can
be seen from Table 3, the longer carbon chain of the aliphatic
aldehydes gave comparatively higher yields than the shorter
ones (entries 1–5). Aromatic aldehydes, for example, benzal-
dehyde, 4-methoxybenzaldehyde and 4-methylbenzaldehyde
could also react with kojic acid easily under the same reaction
conditions (entries 6–8).
A plausible mechanism for the formation of the kojic acid
derivative 3 is shown in Scheme 3. The enolate anion of kojic
acid attacks the carbonyl of the aldehyde to generate 4. The
formation of 4 during the reaction has been confirmed by the
results in Table 1. Under thermal conditions, 4 may generate
intermediate 5, which is easily attacked by the enolate anion of
kojic acid to produce 3.
Under microwave irradiation: The aldehyde (15 mmol) was added
to a solution of kojic acid (1.42 g, 10 mmol), sodium carbonate (1.06
g, 10 mmol) in water (10 mL) and methanol (10 mL) at 70 °C with a
microwave power of 400 W. The reaction mixture was stirred at this
temperature for 40min. The work-up procedures were the same as
described above.
3,3′-Dihydroxy-6,6′-bis(hydroxymethyl)-2,2′-(pentane-1,1-diyl)di-
4H-pyran-4-one (3a): 85% yield.
3,3′-Dihydroxy-6,6′-bis(hydroxymethyl)-2,2′-(propane-1,1-diyl)di-
4H-pyran-4-one (3b): 70% yield; m.p. 214.5–216.1 °C (lit.13 217.5–
218 °C); IR (KBr) νmax: 3459, 3302, 2967, 1654, 1627, 1578, 1442,
In conclusion, we have developed a convenient and efficient
method for the synthesis of kojic acid derivatives by micro-
wave-assisted condensation of kojic acid with aldehydes. This
method has advantages of high yield, simplicity of purification
and short reaction time.
1
1315, 1212 cm−1; H NMR (DMSO-d6, 400 MHz): δ 0.87 (t, J =
7.2 Hz, 3H, CH3), 1.94 (m, 2H, CH2), 4.27 (d, J = 6.0 Hz, 4H, CH2),
4.59 (t, J = 7.2 Hz, 1H, CH), 5.72 (t, J = 6.0 Hz, 2H, OH), 6.29 (s, 2H,
C-5H in pyran ring), 9.01 (s, 2H, OH); ESI-MS: m/z 325 (MH+).
3,3′-Dihydroxy-6,6′-bis(hydroxymethyl)-2,2′-(heptane-1,1-diyl)di-
4H-pyran-4-one (3c): 90% yield; m.p. 150.8–152.6 °C (lit.13 152.6–
153.6 °C); IR (KBr) νmax: 3402, 3302, 2930, 1655, 1618, 1578,
1
1458, 1315, 1214 cm−1; H NMR (DMSO-d6, 400 MHz): δ 0.84 (t,
J = 7.2 Hz, 3H, CH3), 1.23 (m, 8H, CH2), 1.92 (q, J = 7.2 Hz, 2H,
CH2), 4.28 (d, J = 6.4 Hz, 4H, CH2), 4.68 (t, J = 7.2 Hz, 1H, CH), 5.65
(t, J = 6.4 Hz, 2H, OH), 6.28 (s, 2H, C-5H in pyran ring), 9.01 (s, 2H,
OH); ESI-MS: m/z 381 (MH+).
Scheme 2
3,3′-Dihydroxy-6,6′-bis(hydroxymethyl)-2,2′-(nonane-1,1-diyl)di-
4H-pyran-4-one (3d): 88% yield; m.p. 106.3–106.8 °C; IR (KBr)
νmax: 3401, 3280, 2918, 1654, 1618, 1570, 1458, 1215 cm−1; 1H NMR
(DMSO-d6, 400 MHz): δ 0.84 (t, J = 7.2 Hz, 3H, CH3), 1.23 (m, 12H,
CH2), 1.92 (q, J = 7.2 Hz, 2H, CH2), 4.28 (d, J = 6.0 Hz, 4H, CH2),
4.69 (t, J = 7.2 Hz, 1H, CH), 5.62 (t, J = 6.0 Hz, 2H, OH), 6.28
(s, 2H, C-5H in pyran ring), 9.02 (s, 2H, OH); ESI-MS: m/z 409
(MH+), HRMS: Found 431.1678 ([M+Na]+); Calcd 431.1682 for
C21H28NaO8.
3,3′-Dihydroxy-6,6′-bis(hydroxymethyl)-2,2′-(undecane-1,1-diyl)
di-4H-pyran-4-one (3e): 92% yield; m.p. 117–117.4 °C; IR (KBr)
νmax: 3249, 2915, 1656, 1619, 1583, 1453, 1313, 1210, 1090 cm−1; 1H
NMR (DMSO-d6, 400 MHz): δ 0.84 (t, J = 6.8 Hz, 3H, CH3), 1.24 (m,
16H, CH2), 1.91 (q, J = 6.8 Hz, 2H, CH2), 4.28 (d, J = 5.2 Hz, 4H,
CH2), 4.68 (t, J = 8.0 Hz, 1H, CH), 5.62 (t, J = 5.2 Hz, 2H, OH), 6.28
(s, 2H, C-5H in pyran ring), 9.01 (s, 2H, OH); ESI-MS: m/z 437
(MH+); HRMS: Found 459.2007 ([M+Na]+); Calcd 459.1995 for
C23H32NaO8.
Table 3 Microwave-assisted reaction of kojic acid with
aldehydesa
Entry
R
Products
Yield/%b
1
2
3
4
5
6
7
8
n-Bu
Et
n-Hexyl
n-Octyl
n-Decyl
C6H5
3a
3b
3c
3d
3e
3f
85
70
90
88
92
80
88
82
4-CH3C6H4
4-CH3OC6H4
3g
3h
a All reactions were run with kojic acid (10mmol), aldehyde
(15mmol), Na2CO3 (10mmol) in H2O/MeOH (1:1, 20mL) with
400W power at 70 °C for 40 min.
b Isolated yield based on kojic acid.

452 JOURNAL OF CHEMICAL RESEARCH 2012
Scheme 3
3,3′-Dihydroxy-6,6′-bis(hydroxymethyl)-2,2′-(phenylmethane-1,1-
diyl)di-4H-pyran-4-one (3f): 80% yield; m.p. 244–245.3 °C (lit.13
242.4 °C, dec); IR (KBr) νmax: 3434, 2925, 1654, 1619, 1570, 1443
cm−1; 1H NMR (DMSO-d6, 400 MHz): δ 4.25 (d, J = 3.2 Hz, 4H, CH2),
5.65 (br, 2H, OH), 6.06 (s, 1H, CH), 6.32 (s, 2H, C-5H in pyran ring),
7.27–7.37 (m, 5H, Ph), 9.36 (s, 2H, OH); ESI-MS: m/z 373 (MH+).
3,3′-Dihydroxy-6,6′-bis(hydroxymethyl)-2,2′-(4-methyl phenylmethane-
1,1-diyl)di-4H-pyran-4-one (3g): 88% yield; m.p. 223–223.4 °C;
References
1
M. Jimenez, S. Chazarra, J. Escribano, J. Cabanes and F. Garcia-Carmona,
J. Agric. Food Chem., 2001, 49, 4060.
T. Takahashi and M. Miyazawa, Bioorg. Med. Chem. Lett., 2011, 21,
1983.
2
3
4
Y.-J. Kim and H. Uyama, Cell. Mol. Life Sci. 2005, 62, 1707.
Soo MiAhn, Ho Sik Rho, Heung Soo Baek, Yung Hyup Joo, Yong Deog
Hong, Song Seok Shin, Young-Ho Park and Soo Nam Park. Bioorg. Med.
Chem. Lett., 2011, 21, 7466.
1
IR (KBr) νmax: 3322, 2925, 1655, 1619, 1570, 1457 cm−1; H NMR
5
6
7
8
9
H. Mitani, I. Koshiishi, T. Sumita and T. Imanari, Eur. J. Pharmacol., 2001,
411, 169.
S. Kitao, Y. Shimaoka and H. Sekine. Japan Kokai Tokkyo Koho,
56872(Mar. 1, 1994).
Y. Higa and K. Nakajima. Japan Kokai Tokkyo Koho, 319473 (Dec. 25,
1989).
Y.S. Lee, J.H. Park, M.H. Kim, S.H. Seo and H.J. Kim, Arch. Pharm.
Chem. Life Sci., 2006, 399, 111.
(DMSO-d6, 400 MHz): δ 2.27 (s, 3H, CH3) 4.25 (d, J = 2.4 Hz, 4H,
CH2), 5.64 (br, 2H, OH), 6.01 (s, 1H, CH), 6.31 (s, 2H, C-5H in pyran
ring), 7.16 (m, 4H, Ar), 9.33 (br, 2H, OH); ESI-MS: m/z 387 (MH+);
HRMS: Found 387.1081 ([M+H]+) and 409.0904 ([M+Na]+); Calcd
387.1080 and 409.0899 for C20H19O8 and C20H18NaO8, respectively.
3,3′-Dihydroxy-6,6′-bis(hydroxymethyl)-2,2′-(4-methoxyl phenylmethane-
1,1-diyl)di-4H-pyran-4-one (3h): 82% yield; m.p. 235.8–236.7 °C
(lit.20 248–250 °C); IR (KBr) νmax: 3402, 3310, 2930, 1655, 1618 1577,
1458 cm−1; 1H NMR (DMSO-d6, 400 MHz): δ 3.72 (s, 3H, CH3), 4.25
(d, J = 2.0 Hz, 4H, CH2), 5.99 (s, 1H, CH), 6.31 (s, 2H, C-5H in pyran
ring), 6.89 (d, J = 8.8 Hz, 2H, Ar), 7.21 (d, J = 8.8 Hz, 2H, Ar), 9.30
(s, 2H, OH); ESI-MS: m/z 403 (MH+).
B.V.S. Reddy, M.R. Reddy, G. Narasimhulu and J.S. Yadav, Tetrahedron
Lett., 2010, 51, 5677.
10 S.Y. Kwak, H.R. Choi, K.C. Park and Y.S. Lee, J. Pept. Sci., 2011, 17,
791.
11 H.S. Rho, C.S. Lee, S.M. Ahn, Y.D. Hong, S.S. Shin, Y.H. Park and
S.N. Park, Bull. Korean Chem. Soc., 2011, 32, 4411.
12 Xiong, X. and Pirrung, M.C. Org. Lett., 2008, 10, 1151.
13 H.N. Barham and G. Nathan Reed. J. Am. Chem. Soc., 1938, 60, 1541.
14 V. Santagada, F. Frecentese, E. Perissutti, F. Fiorino, B. Severion and
G. Caliendo, Mini. Rev. Med. Chem., 2009, 9, 340.
15 C.O. Kappe and D. Dallinger, Mol. Diversity, 2009, 13, 71.
16 S. Caddick and R. Fitzmaurice, Tetrahedron, 2009, 65, 3325.
17 D. Obermayer, B. Guttmann and C.O. Kappe, Angew. Chem. Int. Ed., 2009,
48, 8321.
This work was supported by the National Natural Science
Foundation of China (No. 20972138) and Qianjiang Scholars
Fund of Zhejiang Province (No. 2010R10051) which are
gratefully acknowledged.
18 Z. Li, Z. Xia and G. Chen, J. Chem. Res., 2011,35, 709.
19 X. Li, X. Zhang, Z.Yu, X. Liu, Q.You and Q. Guo, J. Chem. Res., 2011, 35,
630.
20 M. Yamato, K. Hashigaki, S. Ishikawa, N. Kokubu, Y. Inoue, T. Tsuruo and
T. Tashirot, J. Med. Chem., 1985, 28, 1026.
Received 11 April 2012; accepted 27 April 2012
Paper 1201253 doi: 10.3184/174751912X13383100102119
Published online: 8 August 2012

Copyright of Journal of Chemical Research is the property of Science Reviews 2000 Ltd. and its content may
not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
permission. However, users may print, download, or email articles for individual use.